Grantee Research Project Results
Final Report: The Role of Endocrine Disruptors in Childhood Obesity
EPA Grant Number: R834509C001Subproject: this is subproject number 001 , established and managed by the Center Director under grant R834509
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: The Columbia Center for Children’s Environmental Health
Center Director: Perera, Frederica P.
Title: The Role of Endocrine Disruptors in Childhood Obesity
Investigators: Rundle, Andrew , Whyatt, Robin M.
Institution: Columbia University Mailman School of Public Health
EPA Project Officer: Callan, Richard
Project Period: September 24, 2009 through September 23, 2014 (Extended to September 23, 2015)
RFA: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
- To test whether prenatal and early-life exposures to the endocrine disrupters PAH and BPA predict body size growth trajectories and childhood obesity at age 8-10 years. This will be accomplished by following our ongoing birth cohort to age 8-10 years, measuring height and weight at ages 5, 7, 8-10, body composition at age 7, 8-10, and metabolic syndrome components at age 8-10 years. This work takes advantage of a sophisticated geographic information systems based data on the children's neighborhoods to control for social (e.g. poverty and socio-demographic composition) and physical factors (e.g. play grounds, parks, fast-food) likely to predict childhood obesity.
- To determine whether differences in the methylation status of key genes involved in adipogenesis (PPARv2, C/EBPq, C/EBPli, C/EBP6 and DLK1) and appetite control (FTO) mediate the association between xenobiotic exposures and childhood obesity outcomes. Methylation of these genes was measured in cord white blood cell DNA by pyrosequencing.
Summary/Accomplishments (Outputs/Outcomes):
Aim 1 Part 1: PAH exposure
We have completed study subject enrollment with 400 cohort children having been followed-up through ages 8.5 to 12 years of age. Children provided fasting blood samples and took part in a clinical examination to assess blood lipids, blood glucose, insulin levels, blood pressure, pubertal development and height weight and waist circumference.
Blood samples were sent to the Columbia Biomarkers Core Facility for measurements of blood cholesterol and glucose. Appointments for the children to visit the CCCEH clinical office were scheduled for 2-4 weeks after the blood collection. At the clinical visit, the child's height, weight, waist circumference, body composition and blood pressure were measured. The child underwent a Tanner staging test, and completed a Fels physical activity questionnaire and the modified children's Block FFQ. In addition, a pediatrician provides feedback to the parent on the results of the blood tests, anthropometric measures, and the Tanner staging. Appropriate medical referrals are made for children whose clinical results are outside of norms.
We collaborated with NutritionQuest, the provider of the Block Food Frequency Questionnaire (FFQ), to modify their standard Spanish FFQ for children to include food items from the Dominican diet. Our FFQ is implemented via an online interface.
Since the modified Block FFQ is a new tool, initial statistical analyses of dietary patterns were completed on the first 78 collected data sets using the principle component analyses methods of Hu and colleagues. Two prominent principle components were identified, one loading high on fruits, low fat milk, whole grains, juices, vegetables, and legumes explained 22% of the variance in the data and the second loading high on sandwiches/hamburgers, cold breakfast cereal, processed meats, refined grains and desserts and explained 10% of the variance in the data. These results are consistent with the literature on dietary pattern analyses and the modified Block FFQ thus appears to be collecting valid data.
Analyses of mothers’ exposures to ambient air polycyclic aromatic hydrocarbons (PAH) and obesity outcomes of their children at age 5 and 7 were completed. There was a significant (p< 0.05) association between high prenatal exposure to PAH and higher BMI Z-score and obesity risk at age 5 and with BMI Z-score, obesity risk and fat mass at age 7 (see Table 1). Differences in lean mass (e.g. body mass from organs, bone, muscle tissue) are unrelated to prenatal PAH exposures (Rundle et al., 2012).
BMI Z-score age 5 Beta1, p-value |
BMI Z-score age 7 Beta1, p-value |
%body fat Beta1, p-value |
Fat mass (Kg) Beta1, p-value |
Fat Free Mass (Kg) Beta 1, p-value |
|
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PAH exposure per unit log transformed exposure | 0.20, 0.03 | 0.18, 0.03 | 1.04, 0.03 | 0.60, 0.04 | 0.19, 0.49 |
1Adjusting for birth weight, ethnicity, mother's receipt of public assistance during pregnancy, sex of the child, and maternal pre-pregnancy obesity. |
As part of our work studying the effects of prenatal PAH exposures and childhood obesity we developed and implemented inverse probability weighting (IPW) and marginal structural models (MSM) based methods to assess and adjust for potential biases occurring due to loss to follow-up in the cohort. These methods are being deployed across our studies of obesity, asthma and neurodevelopmental outcomes in the Center cohort. The methods were published as an online supplement to our American Journal of Epidemiology paper (Rundle et al., 2012).
Following up on our 2012 AJE publication showing that prenatal exposures to PAH were associated with higher BMI Z-scores at ages 5 and 7 and with higher fat mass at age 7, we have completed repeated measures analyses of BMI-score at age 5, 7, 9 and 11. Mixed linear growth model analyses show that there is a significant (p < 0.05) effect on the BMI by age intercept at age 5 (0.44 BMI units at age 5 per unit increase in Ln PAH exposure, 95% CI 0.13, 0.75) and no effect on the BMI by age slope. These results indicate that prenatal PAH exposure is associated with higher BMI at age 5, and this higher BMI status continues forward through time without acceleration or flattening of the trajectory. We have also assessed fat mass index (FMI = fat mass in Kg / height in meters2) measured at the 7, 9 and 11 year follow-up waves as a more direct measure of adiposity. Using generalized estimating equation analyses with repeated measures of FMI, we found that higher prenatal PAH exposures were associated with higher FMI (0.30 unit increase in FMI per unit Ln PAH, p = 0.03) and the effects of prenatal PAH exposure on FMI did not vary by wave of follow-up. Similar to the BMI-by-age trajectory results, these analyses suggest that prenatal PAH is associated with FMI attained by age 7, and this higher FMI continues forward through time without a significant acceleration or flattening of the trajectory.
We have also applied latent class growth modeling (LCGM) analyses to the BMI data using the SAS PROJ TRAJ macro. LCGM revealed three major classes of growth classes: Class 1 closely reflects the growth curve of a child at the 50th percentile on the CDC growth charts at age 5 and staying at that percentile through age 11 (55% of children); Class 2 reflects children who were overweight at age 5 and whose growth curve accelerated into the obese category by age 12 ("Overweight-to-obese" trajectory class = 35% of children); and Class 3 reflects children who were already obese at age 5 and whose growth accelerates upwards through age 12 ("Obese-to-highly obese" trajectory class = 10% of children). After adjusting for child sex and potential confounders, children exposed to higher prenatal PAH concentrations were significantly more likely to have growth curves classified as Class 3 as compared to Class 1 (OR = 1.76 per unit Ln PAH, 95% CI 1.07, 2.88).
In terms of dissemination work on the PAH findings, we sent out a series of coordinated press releases when the 2012 AJE paper was published, have made presentations regarding the findings at community forums, and have presented the work in several academic forums. Dr. Rundle participated in the NIEHS Virtual Forum: Childhood Obesity and the Environment. The more recent results looking at growth trajectories have been presented as part of the February 2015 NIEHS/EPA Children’s Centers Webinar series.
Aim 1 Part 2: BPA exposure
We have completed cross-sectional analysis of predictors and correlates of bisphenol A (BPA) levels in urine samples collected from the mothers during pregnancy and from the children at ages 3, 5 and 7. BPA levels in maternal and child age 5 and 7 urine samples are significantly higher for African-Americans as compared to Dominicans. BPA levels were highest in the urine samples collected during summer months from the children at ages 3, 5 and 7. BPA levels in the prenatal, age 3 and 5 urine samples are correlated with eight phthalate metabolites measured in the urine samples (Hoepner et al., 2013). Analyses of maternal urinary BPA levels and birthweight are complete and no associations were observed. Prenatal urinary concentrations of BPA were not associated with child BMI Z scores at age 5 and 7 but were associated with higher waist circumference and FMI at age 7. This work has been submitted to Environmental Health Perspectives and the peer reviewers have recommended that the manuscript be accepted for publication.
Since the launch of our study there has been growing concern in the academic and lay literature about exposures to phthalates and childhood obesity. We have shown that urinary concentrations of phthalates are correlated with urinary concentrations of BPA and thus, phthalates have the potential to confound the associations of BPA with the outcomes of concern. Under separate funding maternal and child urine samples have been analyzed for 9 phthalate metabolites and Dr. Rundle oversaw a T32 Medical Fellow in Pediatric Endocrinology, Dr. Michelle Maresca, in analyzing the phthalate metabolite data and child body size. This work is aligned with our hypotheses that exposures to endocrine disrupting chemicals affect childhood body size, we include the results here in our progress report. We have completed analyses of urinary phthalate concentrations in maternal and child (age 3 and 5) urine samples and child anthropometric outcomes at age 5 and 7. Child anthropometric outcomes are not associated with child urinary metabolite concentrations. However, higher concentrations of non-DEHP metabolites in maternal urine are associated with lower BMI z-scores at ages 5 and 7 and with lower fat mass index and waist circumference at age 7 among boys only. This work was e-published ahead of print in June 2015 in Environmental Health Perspectives; we expect it to appear in print soon. We have also collaborated several of the other Children’s Centers to pool our urinary phthalate and child anthropometric outcome data. A paper based on the pooled analyses has been accepted for publication in the journal Epidemiology.
Airborne PAH concentrations as measured by the personal air-monitors carried by the mothers were not correlated with concentrations of BPA and phthalate metabolites in urine samples collected from the mothers nor with concentrations of these chemicals in urine samples collected from the children. The effects of prenatal PAH exposures on childhood growth are not confounded by exposures to these chemicals.
Aim 2: Methylation Status of Key Genes Involved in Adipogenesis
We completed the assessment of methylation status using pyrosequencing for the PPAR-Gamma and DLK1 genes in cord-blood DNA. Percent methylation scores across 16 CpG sites in PPAR Gamma were associated with child sex, but were not associated with prenatal exposure to PAH measured in air, or with BPA or phthalate metabolite concentrations in maternal urine samples. PPAR Gamma methylation status was also not associated with child anthropometric outcomes. Similarly CpG methylation in DLK1 was not associated with exposures or outcomes.
Additional Work
Linking with the Neurodevelopment Project (PI: Virginia Rauh) we have assessed whether trajectories of development of emotional self-regulation as measured by the Child Behavior Checklist (CBCL) are associated with child obesity risk. The CBCL was administered to the cohort children at ages 3 to 5, 7, 9 and 11 years. The index of deficient self-regulation (DESR) was calculated by combining t-scores on three scales from CBCL: intense emotions (Anxiety/ Depression Scale), aggression (Aggression Scale), and impulsive behavior (Attention Scale). LCGM were then applied to repeated measures of Self-Regulation. Analyses identified two distinct and stable classes of Self-Regulation trajectories, a latent class reflecting "High and stable self-regulation throughout childhood" (82% of children) and a latent class that reflected "Poor self-regulation throughout childhood" (18% of children). Children in the "Poor self-regulation throughout childhood" trajectory class were significantly more likely also to be members of the "Overweight-to-obese" and the "Obese-to-highly obese" trajectory classes identified in the childhood anthropometric data (p=0.03). These analyses show that unhealthy weight gain trajectories are significantly associated with poorer developmental trajectories for emotional self-regulation. In addition we assessed the link between DESR trajectory classes and child physical activity between ages 8.5 and 12 years as measured in the obesity project using the Fels physical activity questionnaire. Children who belonged to the "Poor self-regulation throughout childhood" latent class had significantly lower activity scores for the Fels Total Activity Scale (0.66 scale score points lower, p < 0.01) as compared to participants who belonged to the "High and stable self-regulation throughout childhood" latent class. The deficit in physical activity was largely due to lower activity levels in leisure time; 0.48 scale score points lower on the Fels Leisure Time Scale (p < 0.001).
We have also completed analyses of child anthropometric outcomes and maternal use of antibiotics during pregnancy and mode of delivery and find that c-section birth and antibiotic use are associated with higher BMI z-scores at age 7 (Mueller et al., 2014). We have also completed analyses showing that excessive weight gain during pregnancy is associated with higher BMI z-scores and fat mass in the child at ages 5 and 7 (Widen et al., 2015a). We have also recently published a paper in the American Journal of Clinical Nutrition showing that excessive gestational weight gain among women who were normal weight or mildly overweight before pregnancy is associated with higher weight and % body fat seven years postpartum (Widen et al. 2015b).
References:
Hoepner et al. 2013. Urinary concentrations of bisphenol A in an urban minority birth cohort in New York City, prenatal through age 7 years. Hoepner LA, Whyatt RM, Just AC, Calafat AM, Perera FP, Rundle AG. Environmental Research 2013;122:38-44.
Mueller et al. 2015. Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity. Mueller NT, Whyatt R, Hoepner L, Oberfield S, Dominguez-Bello MG, Widen EM, Hassoun A, Perera F, Rundle A. International Journal of Obesity 2015;39(4):665-670.
Rundle et al. 2012. Association of childhood obesity with maternal exposure to ambient air polycyclic aromatic hydrocarbons during pregnancy. Rundle A, Hoepner L, Hassoun A, Oberfield S, Freyer G, Holmes D, Reyes M, Quinn J, Camann D, Perera F, Whyatt R. American Journal of Epidemiology 2012;175(11):1163-1172.
Widen et al. 2015a. Gestational weight gain and obesity, adiposity and body size in African–American and Dominican children in the Bronx and Northern Manhattan. Widen EM, Whyatt RM, Hoepner LA, Mueller NT, Ramirez‐Carvey J, Oberfield SE, Hassoun A, Perera FP, Gallagher D, Rundle AG. Maternal & Child Nutrition. 2015 Apr 1.
Widen et al. 2015b. Excessive gestational weight gain is associated with long-term body fat and weight retention at 7 y postpartum in African American and Dominican mothers with underweight, normal, and overweight prepregnancy BMI. Widen EM, Whyatt RM, Hoepner LA, Ramirez-Carvey J, Oberfield SE, Hassoun A, Perera FP, Gallagher D, Rundle AG. American Journal of Clinical Nutrition 2015;102(6):1460-1467.
Journal Articles on this Report : 7 Displayed | Download in RIS Format
Other subproject views: | All 19 publications | 7 publications in selected types | All 7 journal articles |
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Other center views: | All 104 publications | 62 publications in selected types | All 60 journal articles |
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Buckley JP, Engel SM, Braun JM, Whyatt RM, Daniels JL, Mendez MA, Richardson DB, Xu Y, Calafat AM, Wolff MS, Lanphear BP, Herring AH, Rundle AG. Prenatal phthalate exposures and body mass index among 4- to 7-year-old children: a pooled analysis. Epidemiology 2016;27(3):449-458. |
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Hoepner LA, Whyatt RM, Just AC, Calafat AM, Perera FP, Rundle AG. Urinary concentrations of bisphenol A in an urban minority birth cohort in New York City, prenatal through age 7 years. Environmental Research 2013;122:38-44. |
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Maresca MM, Hoepner LA, Hassoun A, Oberfield SE, Mooney SJ, Calafat AM, Ramirez J, Freyer G, Perera FP, Whyatt RM, Rundle AG. Prenatal exposure to phthalates and childhood body size in an urban cohort. Environmental Health Perspectives 2015 June 12 [Epub ahead of print], doi:10.1289/ehp.1408750. |
R834509 (2013) R834509C001 (Final) R836154 (2017) |
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Mueller NT, Whyatt R, Hoepner L, Oberfield S, Dominguez-Bello MG, Widen EM, Hassoun A, Perera F, Rundle A. Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity. International Journal of Obesity 2015;39(4):665-670. |
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Rundle A, Hoepner L, Hassoun A, Oberfield S, Freyer G, Holmes D, Reyes M, Quinn J, Camann D, Perera F, Whyatt R. Association of childhood obesity with maternal exposure to ambient air polycyclic aromatic hydrocarbons during pregnancy. American Journal of Epidemiology 2012;175(11):1163-1172. |
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Widen EM, Whyatt RM, Hoepner LA, Ramirez-Carvey J, Oberfield SE, Hassoun A, Perera FP, Gallagher D, Rundle AG. Excessive gestational weight gain is associated with long-term body fat and weight retention at 7 y postpartum in African American and Dominican mothers with underweight, normal, and overweight prepregnancy BMI. American Journal of Clinical Nutrition 2015;102(6):1460-1467. |
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Widen EM, Whyatt RM, Hoepner LA, Mueller NT, Ramirez‐Carvey J, Oberfield SE, Hassoun A, Perera FP, Gallagher D, Rundle AG. Gestational weight gain and obesity, adiposity and body size in African-American and Dominican children in the Bronx and Northern Manhattan. Maternal & Child Nutrition 2016;12(4):918-928. |
R834509C001 (Final) R836154 (2017) |
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Supplemental Keywords:
environmental health, epidemiology, molecular epidemiology, PAH, BPA, prenatal, obesity, metabolic syndrome, BMI, neurodevelopment, children, New York City, NYC;, RFA, Scientific Discipline, Health, INTERNATIONAL COOPERATION, ENVIRONMENTAL MANAGEMENT, POLLUTANTS/TOXICS, Chemicals, Biochemistry, Children's Health, Environmental Policy, Biology, Risk Assessment, health effects, air toxics, developmental neurotoxicity, air pollution, childhood obesity, endocrine disruptors, assessment of exposure, children's vulnerablity, children's environmental health, growth & developmentRelevant Websites:
Columbia Center for Children’s Environmental Health ExitProgress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R834509 The Columbia Center for Children’s Environmental Health Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834509C001 The Role of Endocrine Disruptors in Childhood Obesity
R834509C002 The Role of Endocrine Disruptors in Neurodevelopmental Disorders
R834509C003 The Mechanisms of Endocrine Disruptors in Laboratory Mice
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
7 journal articles for this subproject
Main Center: R834509
104 publications for this center
60 journal articles for this center